| Summary: | Estrogen receptor (ER)-positive progesterone receptor (PR)-negative breast cancers are infrequent but clinically challenging. Despite the volume of genomic data available on these tumors, their biology remains poorly understood. Here, we aimed to identify clinically relevant subclasses of ER+/PR− breast cancers based on their mutational landscape. The Cancer Genomics Data Server was interrogated for mutational and clinical data of all ER+ breast cancers with information on PR status from The Cancer Genome Atlas (TCGA), Memorial Sloan Kettering (MSK), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) projects. Clustering analysis was performed using gplots, ggplot2, and ComplexHeatmap packages. Comparisons between groups were performed using the Student’s t-test and the test of Equal or Given Proportions. Survival curves were built according to the Kaplan⁻Meier method; differences in survival were assessed with the log-rank test. A total of 3570 ER+ breast cancers (PR− n = 959, 27%; PR+ n = 2611, 73%) were analyzed. Mutations in well-known cancer genes such as <em>TP53</em>, <em>GATA3</em>, <em>CDH1</em>, <em>HER2</em>, <em>CDH1</em>, and <em>BRAF</em> were private to or enriched for in PR− tumors. Mutual exclusivity analysis revealed the presence of four molecular clusters with significantly different prognosis on the basis of <em>PIK3CA</em> and <em>TP53</em> status. ER+/PR− breast cancers are genetically heterogeneous and encompass a variety of distinct entities in terms of prognostic and predictive information.
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